Reconsidering Mesenchymal Stem Cell Therapy: From Cellular Identity to Mechanism-Oriented Translation

We read with great interest the recently published articles discussing the therapeutic applications of mesenchymal stem cells (MSCs). Over the past two decades, MSCs have been extensively investigated for their immunomodulatory and regenerative properties, leading to a rapid expansion of preclinical studies and clinical trials across a wide spectrum of diseases[1-4]. Nevertheless, despite the initial enthusiasm, clinical outcomes remain inconsistent and, in many indications, disappointing. One critical issue lies in the biological heterogeneity of MSCs. MSCs derived from different tissue sources, donors, and culture conditions exhibit substantial variability in phenotype, secretory profiles, and functional potency[2, 5]. Although the minimal criteria proposed by the International Society for Cell Therapy provide a useful framework for defining MSC identity, these criteria are insufficient to predict therapeutic efficacy. As a result, MSCs classified under the same definition may represent functionally distinct cell populations with divergent clinical behavior. Equally important is the growing recognition that the therapeutic effects of MSCs are largely mediated by paracrine and immunological mechanisms rather than long-term engraftment or differentiation[6]. Accumulating evidence suggests that short-lived MSCs, apoptotic MSCs, or even MSC-derived extracellular vesicles (EVs) can reproduce many of the observed therapeutic benefits. This paradigm challenges the traditional view of MSCs as “living drugs” and calls for a shift toward mechanism-driven rather than cell-centric therapeutic strategies. Furthermore, limitations in clinical trial design have contributed to the translational gap[7, 8]. Many trials rely on heterogeneous patient populations, poorly defined endpoints, and insufficient consideration of disease stage or immune microenvironment. Without appropriate patient stratification and biologically relevant outcome measures, even well-characterized MSC products may fail to demonstrate efficacy in late-phase trials[9]. In light of these challenges, we believe the field would benefit from a strategic recalibration. Future research should prioritize (i) functional potency assays linked to defined mechanisms of action, (ii) standardized manufacturing and release criteria beyond surface marker expression, and (iii) rational clinical trial designs that align MSC biology with disease pathophysiology. In parallel, cell-free approaches such as MSC-derived EVs merit serious consideration as more controllable and scalable therapeutic modalities.